Semicarbazide derivatives and the use thereof as antithrombotics

ABSTRACT

Novel compounds of the formula I, in which R, R 1 , R 2  and R 3  are as defined in patent claim 1, are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.

The invention relates to compounds of the formula I

in which

-   R is C(═NH)—NH₂, which may also be monosubstituted by OH, OCOOA,    OCOO(CH₂)_(n)N(A)₂, OCOO(CH₂)_(m)-Het, COO(CH₂)_(n)N(A)₂,    COO(CH₂)_(m)-Het, CO—C(A)₂—R⁴, COOA, COSA, COOAr or COOAr′, or is    CH₂NH₂,-   R¹ is X, Ar or Ar′,-   R² is phenyl which is monosubstituted by S(O)_(p)A, S(O)_(p)NHA,    CF₃, COOA or CH₂NHA,-   R³ is H or Hal,-   R⁴ is —CHal₃, O(C═O)A or-   Ar is phenyl which is unsubstituted or monosubstituted,    disubstituted or trisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂,    CF₃, CN, Hal, COA, NHCOA, COOA, CONH₂, CONHA, CONA₂, S(O)_(p)A,    S(O)_(p)NH₂, S(O)_(p)NHA or S(O)_(p)NA₂,-   Ar′ is —(CH₂)_(n)—Ar,-   A is H, or unbranched, branched or cyclic alkyl having 1-20 carbon    atoms,-   X is unbranched or branched alkyl having 1-20 carbon atoms, in which    one or two CH₂ groups may be replaced by O or S atoms and/or also    1-7H atoms may be replaced by F,-   Het is a monocyclic or bicyclic saturated, unsaturated or aromatic    heterocyclic radical having from 1 to 4 N, O and/or S atoms, which    may be unsubstituted or monosubstituted or disubstituted by A,-   Hal is F, Cl, Br or I,-   n is 1, 2, 3, 4, 5 or 6,-   m is 1, 2, 3, 4, 5 or 6,-   P is 0, 1 or 2,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and salts thereofhave very valuable pharmacological properties and are well tolerated. Inparticular, they exhibit factor Xa-inhibiting properties and cantherefore be employed for combating and preventing thromboembolicdiseases, such as thrombosis, myocardial infarction, arteriosclerosis,inflammation, apoplexy, angina pectoris, restenosis after angioplastyand claudicatio intermittens.

The compounds of the formula I according to the invention mayfurthermore be inhibitors of the coagulation factors factor VIIa, factorIXa and thrombin in the blood coagulation cascade.

Aromatic amidine derivatives having an antithrombotic action aredisclosed, for example, in EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO00/71515 or WO 00/71516. Cyclic guanidines for the treatment ofthromboembolic diseases are described, for example, in WO 97/08165.Aromatic heterocyclic compounds having factor Xa-inhibitory activity aredisclosed, for example, in WO 96/10022. SubstitutedN-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xainhibitors are described in WO 96/40679.

Regioisomeric compounds of the derivatives according to the inventionare described in DE 100407.83.8 (compounds of the formula 7 in SynthesisScheme 1).

The antithrombotic and anticoagulant effect of the compounds accordingto the invention is attributed to the inhibitory action againstactivated coagulation protease, known by the name factor Xa, or to theinhibition of other activated serine proteases, such as factor VIIa,factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process ofblood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic diseases. However, inhibition of thrombin may inhibit thefibrin formation involved in thrombus formation. The inhibition ofthrombin can be measured, for example, by the method of G. F. Cousins etal. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent the formation of thrombin.

The compounds of the formula I according to the invention and saltsthereof engage in the blood coagulation process by inhibiting factor Xaand thus inhibit the formation of thrombi.

The inhibition of factor Xa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Hauptmann et al. in Thrombosisand Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example, by the methodof T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

Coagulation factor VIIa initiates the extrinsic part of the coagulationcascade after binding to tissue factor and contributes to the activationof factor X to give factor Xa. Inhibition of factor VIIa thus preventsthe formation of factor Xa and thus subsequent thrombin formation.

The inhibition of factor VIIa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A conventional method for the measurement of the inhibition of factorVIIa is described, for example, by H. F. Ronning et al. in ThrombosisResearch 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascadeand is likewise involved in the activation of factor X to give factorXa. Inhibition of factor IXa can therefore prevent the formation offactor Xa in a different way.

The inhibition of factor IXa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Chang et al. in Journal ofBiological Chemistry 1998, 273, 12089-12094.

The compounds according to the invention may furthermore be used for thetreatment of tumours, tumour diseases and/or tumour metastases.

A correlation between tissue factor TF/factor VIIa and the developmentof various types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59.

The publications listed below describe an antitumoral action of TF-VIIand factor Xa inhibitors for various types of tumour:

-   K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;-   E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);-   B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);-   M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine, in particular for thetreatment and prevention of thromboembolic diseases, such as thrombosis,myocardial infarction, arteriosclerosis, inflammation, apoplexy, anginapectoris, restenosis after angioplasty, claudicatio intermittens, venousthrombosis, pulmonary embolism, arterial thrombosis, myocardialischaemia, unstable angina and strokes based on thrombosis.

The compounds according to the invention are also employed for thetreatment or prophylaxis of atherosclerotic diseases, such as coronaryarterial disease, cerebral arterial disease or peripheral arterialdisease.

The compounds are also employed in combination with other thrombolyticagents in the case of myocardial infarction, furthermore for prophylaxisfor reocclusion after thrombolysis, percutaneous transluminalangioplasty (PTCA) and coronary bypass operations.

The compounds according to the invention are furthermore used for theprevention of rethrombosis in microsurgery, furthermore asanticoagulants in connection with artificial organs or in haemodialysis.

The compounds are furthermore used in the cleaning of catheters andmedical aids in vivo in patients, or as anticoagulants for thepreservation of blood, plasma and other blood products in vitro. Thecompounds according to the invention are furthermore used for diseasesin which blood coagulation makes a crucial contribution to the course ofthe disease or represents a source of secondary pathology, such as, forexample, in cancer, including metastasis, inflammatory diseases,including arthritis, and diabetes.

The compounds according to the invention are furthermore used for thetreatment of migraine (F. Morales-Asin et al., Headache, 40, 2000,45-47).

In the treatment of the diseases described, the compounds according tothe invention are also employed in combination with otherthrombolytically active compounds, such as, for example, with “tissueplasminogen activator” t-PA, modified t-PA, streptokinase or urokinase.The compounds according to the invention are administered either at thesame time as or before or after the other substances mentioned.

Particular preference is given to simultaneous administration withaspirin in order to prevent recurrence of the thrombus formation.

The compounds according to the invention are also used in combinationwith blood platelet glycoprotein receptor (IIb/IIIa) antagonists, whichinhibit blood platelet aggregation.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-9 and pharmaceutically usable derivatives,solvates and stereoisomers thereof, characterised in that

-   a) they are liberated from one of their functional derivatives by    treatment with a solvolysing and/or hydrogenolysing agent by-   i) liberating an amidino group from its oxadiazole derivative or    oxazolidinone derivative by hydrogenolysis or solvolysis,-   ii) replacing a conventional amino-protecting group with hydrogen by    treatment with a solvolysing or hydrogenolysing agent or liberating    an amino group protected by a conventional protecting group,-   b) a radical R is converted into another radical R by    -   i) converting a cyano group into an amidino group,    -   ii) reducing an amide group to an aminoalkyl group,    -   iii) reducing a cyano group to an aminoalkyl group,        and/or a base or acid of the formula I is converted into one of        its salts.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, monohydrates or dihydrates or alcoholates.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified with, for example, alkyl or acyl groups, sugarsor oligopeptides and which are rapidly cleaved in the organism to givethe effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, such as, for example, A,their meanings are independent of one another.

Above and below, the radicals or parameters R, R¹, R² and R³ are asdefined under the formula I, unless expressly stated otherwise.

X is alkyl, is unbranched (linear), branched or cyclic, and has 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbonatoms. X is preferably methyl, furthermore ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-,2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermorepreferably, for example, trifluoromethyl.

X is very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl,trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl.

Cyclic alkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

A is alkyl, is unbranched (linear), branched or cyclic, and has 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbonatoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-,2- or 3-methylbutyl, 1,1-1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermorepreferably, for example, trifluoromethyl.

A is very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl.

Alkylene is preferably methylene, ethylene, propylene, butylene,pentylene or hexylene, furthermore branched alkylene.

—COA (acyl) is preferably acetyl, propionyl, furthermore also butyryl,pentanoyl, hexanoyl or, for example, benzoyl.

Hal is preferably F, Cl or Br, but also I.

The invention also relates, in particular, to the —C(═NH)—NH₂ compoundsof the formula I which are substituted by —COA, —COOA, —OH or by aconventional amino-protecting group.

R is preferably amidino, which may also be substituted by OH, or isCH₂NH₂.

R¹ is preferably phenyl, benzyl or alkyl having 1, 2, 3, 4, 5, 6 or 7carbon atoms,

R² is preferably a phenyl radical which is monosubstituted byalkylsulfonyl [S(O)₂A] or aminosulfonyl [S(O)₂NHA], where, inparticular, the substituents SO₂CH₃ or SO₂NH₂ are preferred.

R³ is preferably H or F.

Ar is, for example, unsubstituted phenyl, furthermore preferably phenylwhich is, for example, monosubstituted, disubstituted or trisubstitutedby A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl,propionyl, trifluoromethyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, sulfonamido, methylsulfonamido,ethylsulfonamido, propylsulfonamido, butylsulfonamido,dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl,ethoxycarbonyl or phenyl which is monosubstituted, disubstituted ortrisubstituted by aminocarbonyl.

Ar is very particularly preferably unsubstituted phenyl.

Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Het can thus, for example, also be 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, 4- or 5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, 4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, 4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het is preferably a monocyclic saturated or unsaturated heterocyclicradical having 1 or 2 N and/or O atoms, which may be unsubstituted ormonosubstituted or disubstituted by A.

Het is very particularly preferably pyridyl, pyrimidinyl,morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl oroxazolidin-3-yl.

The compounds of the formula I may have one or more chiral centres andtherefore occur in various stereoisomeric forms. The formula I coversall these forms.

Accordingly, the invention relates in particular to the compounds of theformula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ie, which conformto the formula I and in which the radicals not designated in greaterdetail are as defined under the formula I, but in which

-   in Ia R is amidino, which may also be substituted by OH, or is    CH₂NH₂;-   in Ib R¹ is phenyl, benzyl or alkyl having 1, 2, 3, 4, 5, 6 or 7    carbon atoms;-   in Ic R³ is H or F;-   in Id R² is a phenyl radical which is monosubstituted by    alkylsulfonyl or aminosulfonyl;-   in Ie R² is a phenyl radical which is monosubstituted by    methylsulfonyl or aminosulfonyl;    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

Compounds of the formula I can preferably be obtained by liberatingcompounds of the formula I from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the formula I, but contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bonded to an N atom, in particular thosewhich carry an R′—N group, in which R′ is an amino-protecting group,instead of an HN group, and/or those which carry a hydroxyl-protectinggroup instead of the H atom of a hydroxyl group, for example those whichconform to the formula I, but carry a —COOR″ group, in which R″ is ahydroxyl-protecting group, instead of a —COOH group.

Preferred starting materials are also the oxadiazole derivatives, whichcan be converted into the corresponding amidino compounds.

The amidino group can be liberated from its oxadiazole derivative by,for example, treatment with hydrogen in the presence of a catalyst (forexample Raney nickel). Suitable solvents are those indicated below, inparticular alcohols, such as methanol or ethanol, organic acids, such asacetic acid or propionic acid, or mixtures thereof. The hydrogenolysisis generally carried out at temperatures between about 0 and 100° andpressures between about 1 and 200 bar, preferably at 20-30° (roomtemperature) and 1-10 bar.

The oxadiazole group is introduced, for example, by reaction of thecyano compounds with hydroxylamine and reaction with phosgene, dialkylcarbonate, chloroformic acid esters, N,N′-carbonyldiimidazole or aceticanhydride.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which can easily be removed after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size are furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl, tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkoxycarbonyl, such asCBZ (“carbobenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but which can easily be removed after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are the above-mentioned unsubstitutedor substituted aryl, aralkyl or acyl groups, furthermore also alkylgroups. The nature and size of the hydroxyl-protecting groups is notcrucial since they are removed again after the desired chemical reactionor reaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 500, preferably between 15 and 300 (room temperature).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Hydrogenolytically removable protecting groups (for example CBZ, benzylor the liberation of the amidino group from its oxadiazole derivative))can be cleaved off, for example, by treatment with hydrogen in thepresence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid oracetic acid; nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents.

A cyano group is converted into an amidino group by reaction with, forexample, hydroxylamine followed by reduction of the N-hydroxyamidineusing hydrogen in the presence of a catalyst, such as, for example,Pd/C. In order to prepare an amidine of the formula I, it is alsopossible to adduct ammonia onto a nitrile. The adduction is preferablycarried out in a number of steps by, in a manner known per se, a)converting the nitrile into a thioamide using H₂S, converting thethioamide into the corresponding S-alkylimidothioester using analkylating agent, for example CH₃I, and reacting the thioester in turnwith NH₃ to give the amidine, b) converting the nitrile into thecorresponding imidoester using an alcohol, for example ethanol, in thepresence of HCl, and treating the imidoester with ammonia (Pinnersynthesis), or c) reacting the nitrile with lithiumbis(trimethylsilyl)amide, and subsequently hydrolysing the product.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, or reacted with CH₃—C(═NH)—OEt,advantageously in an inert solvent, such as dichloromethane or THFand/or in the presence of a base, such as triethylamine or pyridine, attemperatures between −60 and +30°.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, or into the corresponding ammonium salts using bases (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate).

It is also possible to use physiologically acceptable organic bases,such as, for example, ethanolamine.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of pharmaceutical preparations, in particular bynon-chemical methods. They can be converted here into a suitable dosageform together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and, if desired, in combination with one or morefurther active ingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

These preparations can be used in human or veterinary medicine. Suitableexcipients are organic or inorganic substances which are suitable forenteral (for example oral), parenteral or topical administration and donot react with the novel compounds, for example water, vegetable oils,benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatine, carbohydrates, such as lactose or starch,magnesium stearate, talc or Vaseline. Suitable for oral administrationare, in particular, tablets, pills, coated tablets, capsules, powders,granules, syrups, juices or drops, suitable for rectal administrationare suppositories, suitable for parenteral administration are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical application areointments, creams or powders or also as nasal sprays. The novelcompounds may also be lyophilised and the resultant lyophilisates used,for example, to prepare injection preparations. The preparationsindicated may be sterilised and/or comprise adjuvants, such aslubricants, preservatives, stabilisers and/or wetting agents,emulsifying agents, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

The compounds of the formula I and physiologically acceptable saltsthereof can be used for combating and preventing thromboembolicdiseases, such as thrombosis, myocardial infarction, arteriosclerosis,inflammation, apoplexy, angina pectoris, restenosis after angioplastyand claudicatio intermittens, migraine, tumours, tumour diseases and/ortumour metastases.

In general, the substances according to the invention are preferablyadministered in doses between about 1 and 500 mg, in particular between5 and 100 mg, per dosage unit. The daily dose is preferably betweenabout 0.02 and 10 mg/kg of body weight. However, the specific dose foreach patient depends on a wide variety of factors, for example on theefficacy of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, medicament combination andseverity of the particular disease to which the therapy applies. Oraladministration is preferred.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules each containing an effective amount of a compound of theformula I and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament in dissolved orlyophilised form.

The invention furthermore relates to the use of compounds of the formulaI and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios,

for the preparation of a medicament for the treatment of thromboses,myocardial infarction, arteriosclerosis, inflammation, apoplexy, anginapectoris, restenosis after angioplasty, claudicatio intermittens,migraine, tumours, tumour diseases and/or tumour metastases,

in combination with at least one further medicament active ingredient.

Above and below, all temperatures are given in ° C. In the followingexamples, “conventional work-up” means that water is added if necessary,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS):

-   -   EI (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺ (unless specified        otherwise)

EXAMPLE 1 Preparation of1-(3-N-hydroxyamidinophenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide81-(3-amidinophenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide91-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide10 in Accordance with Synthesis Scheme 1

Reaction Conditions for Synthesis Scheme 1:

Step 1.20.0 g (75.384 mmol) of3-fluoro-2′-methanesulfonylbiphenyl-4-yl-amine 2 are dissolved in 300 mlof THF, and 9.149 ml (75.384 mmol) of trichloromethyl chloroformate areadded dropwise at RT with stirring. The reaction mixture is subsequentlyrefluxed for 3 hours, giving the desired isocyanate 3.10.037 g (75.384mmol) of 3-hydrazinobenzonitrile 1 are added to this reaction mixture,which is refluxed for 4 hours and then subjected to conventionalwork-up, giving 28.3 g (88.4%) of 4 as white crystals; MS(EI)=424.

Step 2. 9.2 g (21.674 mmol) of 4 are dissolved in 40.0 ml of DCM, 4.33 g(23.842 mmol) of copper(II) acetate and 1.924 ml (23.842 mmol) ofpyridine are added, and the mixture is stirred at RT for 18 hours.Conventional work-up gives 9.0 g (98.2%) of 5 as yellow crystals;MS(EI)=422.

Step 3. 4.7 g (11.13 mmol) of 5 are dissolved in 100 ml of THF andcooled to −70° C., and 13.351 ml (13.351 mmol) of phenylmagnesiumbromide (1 M in THF) are added dropwise under a nitrogen atmosphere andwith stirring. After a further 5 hours at −70° C., the mixture isallowed to warm to RT overnight and is subsequently subjected toconventional work-up, giving 660 mg (11.9%) of 6 and 1.3 g (23.3%) ofregioisomer 7; MS(EI)=500.

Step 4. [=Hydroxyamidine]. 600 mg (1.199 mmol) of 6 are dissolved in30.0 ml of EtOH, 0.665 ml (4.796 mmol) of triethylamine and 0.333 g(4.796 mmol) of hydroxylammonium chloride are added, and the mixture isrefluxed for 4 hours. Conventional work-up gives 420 mg (65.6%) of whitecrystals 8; MS(EI)=533.

Step 5. [=Amidine]. 300 mg (0.562 mmol) of 8 in 10 ml of methanol/THF(1:1) and 0.5 ml of glacial acetic acid are hydrogenated at RT with 12.6ml of hydrogen using 0.3 g of Raney nickel (water-moist). Conventionalwork-up gives 170 mg (52.4%) of crystals 9; MS(ESI)=518.

Step 6. [=Benzylamine]. 410 mg (0.819 mmol) of 6 in 5 ml of 10%methanolic ammonia solution are hydrogenated over 0.2 g of Raney nickel(water-moist). After work-up, the crude product is dissolved in 2 ml ofmethanol, and 5 ml of HCl in diethyl ether (c=2 mol/1) are added.Conventional work-up gives 310 mg of crystals 10; MS(ESI)=505.

Alternative Synthesis Scheme

EXAMPLE 2

The following compounds are obtained analogously to Example 1

-   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-aminomethylphenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,-   1-(3-aminomethylphenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-aminomethylphenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-propylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-propylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-aminosulfonylbiphenyl-4-yl)-1-propylsemicarbazide,-   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-benzylsemicarbazide,-   1-(3-aminomethylphenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-propylsemicarbazide,-   1-(3-N-hydroxyamidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-propylsemicarbazide,-   1-(3-amidinophenyl)-4-(2′-methylsulfonylbiphenyl-4-yl)-1-propylsemicarbazide.    Pharmacological Data

Affinity to Receptors TABLE 1 Compound No. FXa-IC₅₀ [M] TF/FVIIa-IC₅₀[M] 8 3.8E−6 8.8E−6 9 2.8E−8 1.2E−8 10 2.4E−6 4.2E−6

The examples below relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced in aconventional manner into hard gelatine capsules in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R is C(═NH)—NH₂, which may also be monosubstituted by OH,OCOOA, OCOO(CH₂)_(n)N(A)₂, OCOO(CH₂)_(m)-Het, COO(CH₂)_(n)N(A)₂,COO(CH₂)_(m)-Het, CO—C(A)₂—R⁴, COOA, COSA, COOAr or COOAr′, or isCH₂NH₂,

R¹ is unbranched or branched alkyl having 1-20 carbon atoms, in whichone or two CH₂ groups may be replaced by O or S atoms and/or also 1-7Hatoms may be replaced by F, or is Ar or Ar′, R² is phenyl which ismonosubstituted by S(O)_(p)A, S(O)_(p)NHA, CF₃, COOA or CH₂NHA, R³ is Hor Hal, R⁴ is —CHal₃, O(C═O)A or

Ar is phenyl which is unsubstituted or monosubstituted, disubstituted ortrisubstituted by A, OH, OA, NH₂, NHA, NA₂, NO₂, CF₃, CN, Hal, COA,NHCOA, COOA, CONH₂, CONHA, CONA₂, S(O)_(p)A, S(O)_(p)NH₂, S(O)_(p)NHA orS(O)_(p)NA₂, Ar′ is —(CH₂)_(n)—Ar, A is H, or unbranched, branched orcyclic alkyl having 1-20 carbon atoms, Het is a monocyclic or bicyclicsaturated, unsaturated or aromatic heterocyclic radical having from 1 to4 N, O and/or S atoms, which may be unsubstituted or monosubstituted ordisubstituted by A, Hal is F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is1, 2, 3, 4, 5 or 6, p is 0, 1 or 2, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 2. Compounds according to claim 1, in which R isamidino, which may also be substituted by OH, or is CH₂NH₂, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 3. Compounds according toclaim 1, in which R¹ is phenyl, benzyl or alkyl having 1, 2, 3, 4, 5, 6or 7 carbon atoms, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 4.Compounds according to claim 1, in which R³ is H or F, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 5. Compounds according toclaim 1, in which R² is a phenyl radical which is monosubstituted byalkylsulfonyl or aminosulfonyl, and pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios.
 6. Compounds according to claim 1, in which R² is a phenylradical which is monosubstituted by methylsulfonyl or aminosulfonyl, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 7. Compounds according toclaim 1, selected from the group consisting of1-(3-N-hydroxyamidinophenyl-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,1-(3-amidinophenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,1-(3-aminomethylphenyl)-4-(3-fluoro-2′-methylsulfonylbiphenyl-4-yl)-1-phenylsemicarbazide,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 8. Process for thepreparation of compounds of the formula I according to claim 1 andpharmaceutically usable derivatives, solvates and stereoisomers thereof,characterised in that a) they are liberated from one of their functionalderivatives by treatment with a solvolysing and/or hydrogenolysing agentby i) liberating an amidino group from its oxadiazole derivative oroxazolidinone derivative by hydrogenolysis or solvolysis, ii) replacinga conventional amino-protecting group with hydrogen by treatment with asolvolysing or hydrogenolysing agent or liberating an amino groupprotected by a conventional protecting group, b) a radical R¹, R² and/orY is converted into another radical R¹, R² and/or Y by i) converting acyano group into an amidino group, ii) reducing an amide group to anaminoalkyl group, iii) reducing a cyano group to an aminoalkyl group,and/or a base or acid of the formula I is converted into one of itssalts.
 9. Compounds of the formula I according to claim 1 as inhibitorsof coagulation factor Xa.
 10. Compounds of the formula I according toclaim 1 as inhibitors of coagulation factor VIIa.
 11. Medicamentscomprising at least one compound of the formula I according to claim 1and/or pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios, and optionallyexcipients and/or adjuvants.
 12. Medicaments comprising at least onecompound of the formula I according to one claim 1 and/orpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, and at least one furthermedicament active ingredient.
 13. Use of compounds according to claim 1and/or physiologically acceptable salts and solvates thereof for thepreparation of a medicament for the treatment of thromboses, myocardialinfarction, arteriosclerosis, inflammation, apoplexy, angina pectoris,restenosis after angioplasty, claudicatio intermittens, migraine,tumours, tumour diseases and/or tumour metastases.
 14. Set (kit)consisting of separate packs of (a) an effective amount of a compound ofthe formula I according to claim 1 and/or pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and (b) an effective amount of a furthermedicament active ingredient.
 15. Use of compounds of the formula Iaccording to claim 1 and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, for the preparation of a medicament for the treatment ofthromboses, myocardial infarction, arteriosclerosis, inflammation,apoplexy, angina pectoris, restenosis after angioplasty, claudicatiointermittens, migraine, tumours, tumour diseases and/or tumourmetastases, in combination with at least one further medicament activeingredient.